Filoviruses and arenaviruses are two major families of lethal hemorrhagic fever viruses for which no vaccines or treatments are currently available. Previous work by several investigators involved in this proposal has unequivocally demonstrated the feasibility of protecting non-human primates against viral challenge with immunotherapy. This highly translational proposal will identify the most effective monoclonal antibodies and from them, create broad-spectrum antibody cocktails for pre- or post-exposure use. To achieve this goal, we will leverage the consortium's large collection of anti-filovirus and anti-arenavirus antibodies, as well as new antibodies to be derived from ongoing and proposed discovery efforts. However, it will not be feasible to test each of our hundreds of candidate antibodies and thousands of potential antibody combinations in animals without some initial in vitro downselection. To generate a manageable set of candidate antibodies and cocktails, Core C (working together the three project teams and the Gore D team) will categorize antibodies into structural and functional groups, perform rules-based triage of antibody candidates, and design antibody cocktails based on antiviral activity and functional diversity. Finally and importantly. Core C will prioritize candidate cocktails based on their susceptibility to escape mutations, and will, together with Core D, identify antibodies most resistant to escape, as well as replacement antibodies that will mop up escaping virions. In addition to selection of the most effective single antibodies and cocktails of antibodies to forward for patient use, this Gore will provide essential information that addresses major, basic knowledge gaps in the field. Our comprehensive analysis will illustrate which epitopes lead to the most effective protection, which in vitro assays are the best predictors of in vivo efficacy, and which epitopes lead to broad-spectrum reactivity and protection.